The IL-17 family of cytokines presently includes IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. All IL-17 family members have four highly conserved cysteine residues that are involved in the formation of intrachain disulfide linkages and have two or more cysteine residues that may be involved in interchain disulfide linkages. Members of the IL-17 family have no sequence similarity to any other known cytokines. However, a viral homologue of IL-17A was found in open reading frame 13 of herpesvirus saimiri (Yao, Z. et al., Immunity, 3:811, 1995) and has 72% amino acid residue identity to human IL-17A. Multiple functions have been reported for the IL-17 family members that mainly involve regulation of the immune response.
Interleukin 17 (IL-17, also referred to as IL-17A) is a 20-30 kD homodimeric glycoprotein produced predominantly by activated CD4+ T cells and functions as a proinflammatory cytokine. When a particular IL-17 family member is referred to simply as “IL-17,” it is understood that the family member referred to is IL-17A. IL-17 is secreted by activated T cells at sites of inflammation not in the systemic circulation. IL-17 binds to a type I transmembrane receptor termed IL-17R which is a large ubiquitously expressed protein that demonstrates no significant sequence similarity to other known cytokine receptors. IL-17 has multiple biologic properties including upregulating adhesion molecules and inducing the production of multiple inflammatory cytokines and chemokines from various cell types including synoviocytes, chondroctes, fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages. Also, IL-17 induces recruitment of neutrophils to an inflammatory site through induction of chemokine release, stimulates production of prostaglandins and metalloproteinases, and inhibits proteoglycan synthesis. Furthermore, IL-17 plays an important role in the maturation of hematopoietic progenitor cells. It has been demonstrated that IL-17 has signaling roles in different organs and tissues including lung, articular cartilage, bone, brain, hematopoietic cells, kidney, skin and intestine. For a review of IL-17 bioactivity see, e.g., Kolls and Linden, Immunity 21:467-476, 2004, or Fossiez, et al. Int. Rev. Immunol. 16:541, 1998.
Increased levels of IL-17 (i.e., IL-17A) have been associated with several conditions, diseases or disorders including airway inflammation, rheumatoid arthritis (“RA”), osteoarthritis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disorder (“IBD”), allograft rejection, psoriasis, certain types of cancer, angiogenesis, atherosclerosis and multiple sclerosis (“MS”) (for a review see Witkowski, et al, Cell. Mol. Life. Sci. 61:567-579, 2004). Both IL-17 and IL-17R are up-regulated in the synovial tissue of RA patients. Blocking an IL-17 bioactivity by binding an IL-17 specific antibody or soluble receptor to IL-17 reduces inflammation and bone erosion in various animal arthritis models. (See, e.g., Lubberts et al, Arthritis & Rheumatism, 50:650-659, 2004). Furthermore, IL-17 has IL-1β independent effects on collagen matrix breakdown and inflammation and joint damage, while IL-17 has synergy with TNF-α to amplify inflammation.
Thus, given its localized distribution at the site of inflammation, IL-17 appears to be a novel target for the treatment of RA and other inflammatory or autoimmune diseases with a potentially greater safety profile than drugs that target the systemic circulation of pro-inflammatory cytokines such as TNF-α. Current FDA approved bioproducts (ENBREL®, REMICADE® and HUMIRA® antibodies) that bind to and neutralize TNF-α have demonstrated efficacy in reducing signs and symptoms of RA and in slowing progression of the disease in a subset of RA patients. However, not all RA patients respond equally to inhibition of a TNF-α bioactivity with these bioproducts. Additionally, IL-17 mRNA is increased in multiple sclerosis lesions and in mononuclear cells in the blood and cerebrospinal fluid of MS patients, particularly during clinical exacerbation. Accordingly, there is a need for compositions that antagonize or neutralize the activity of IL-17 in order to treat disorders, diseases or conditions wherein the presence of IL-17 bioactivity causes or contributes to an undesirable pathological effect or wherein a decrease in IL-17 bioactivity contributes to a desirable therapeutic effect, including inflammatory disorders, cell proliferative and developmental disorders and autoimmune disorders such as RA and MS and IBD.
There is a need for a neutralizing anti-IL-17 antibody that specifically binds IL-17 of human origin as well as IL-17 of a non-human mammal thereby allowing the antibody to be used in preclinical and clinical in vivo studies. Furthermore, there is a need for an IL-17-specific antibody which binds IL-17 with a high affinity and/or has a slow off rate thereby allowing the effective therapeutic dose to be minimized resulting in less frequent dosing with such an antibody than with an antibody that binds IL-17 with a lesser affinity (i.e., a higher KD) and/or has a faster off rate. A high affinity IL-17-specific antibody is also desirable in that it may allow the antibody to be administered to a patient subcutaneously rather than intravenously. There is also a need for an IL-17-specific antibody with a low IC50 value in an IL-17 bioactivity assay in order to generate a therapeutic anti-IL-17 antibody with a minimum effective therapeutic dose. It is also desirable to provide an antibody specific to IL-17 where an immune response to the antibody evoked by a patient receiving the antibody is reduced to a minimum. The present invention satisfies these needs and provides related advantages.